Mechanism of Pacing-Induced Ventricular Fibrillation
in the Infarcted Human Heart
Anthony W.C. Chow, MD, MRCP; Oliver R. Segal, MRCP;
D. Wyn Davies, MD, FRCP; Nicholas S. Peters, MD, FRCP
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Background—The mechanisms by which ventricular fibrillation (VF) is initiated in the infarcted human heart have not
been defined.
Methods and Results—Left ventricular noncontact mapping of 8 episodes of pacing-induced VF in 6 patients (age
64.8⫾7.9 years, with previous myocardial infraction and left ventricular ejection fraction of 36⫾4%) undergoing
ventricular tachycardia (VT) ablation revealed a consistent mechanism of VF induction. Whether during VT or sinus
rhythm, the first of a train of paced extrastimuli to capture the LV produced an arc or arcs of functional block at regions
bordering scar. With subsequent extrastimuli, the arcs elongated to circumscribe an enlarging area of increasingly late
activation, with reentry through part of this functional (unidirectional) block leading to wavefront fragmentation and VF.
These regions had longer fibrillation intervals (263⫾63 ms) than remote LV regions (209⫾23.4 ms; P⬍0.0001),
implying longer refractory periods, and in 6 of the 8 VF episodes, these regions correlated with VT exit sites. In each
of the 2 patients with 2 episodes of VF, both episodes formed arcs of functional block in the same location, despite
pacing from different sites.
Conclusions—Pacing-induced VF in the infarcted human heart is initiated by the development of functional lines of block
dictated by the properties of a particular region of myocardium characterized by longer refractory periods, at or near VT
circuit exit sites. Identification of these characteristic properties may help stratify risk of arrhythmic death and explain
the potential for VT ablation to modify risk of VF in the infarcted heart. (Circulation. 2004;110:1725-1730.)
Key Words: ventricles 䡲 fibrillation 䡲 mapping 䡲 infarction
S
ustained ventricular tachycardia (VT) in the infarcted
heart can destabilize spontaneously and in so doing may
terminate, accelerate, change morphology, or degenerate to
ventricular fibrillation (VF).1–3 Thus, the inherent instabilities
in the arrhythmia substrate dictate the spectrum of clinical
behavior of human VT, which ranges from asymptomatic
self-limiting episodes to abrupt sudden death due to degeneration to VF. But what dictates whether an individual VT
will terminate or degenerate, how this might be identified,
and the mechanism by which VF evolves remains unknown.
Understanding of these determinants may provide the prospect of risk assessment and a strategy for prevention.
Computer models4 and animal data5– 8 on VF initiation
have shown that there is no critical coupling interval that
provokes VF. Initiation of fibrillatory activity in humans also
appears to occur distant from the site of pacing.9 These
observations suggest that the fibrillatory tendency is dictated
by properties of the ventricular myocardium in a particular
region of the diseased ventricle, but the lack of spatial
resolution with conventional intracardiac electrode catheters
has precluded further investigation to provide mechanistic
insight into these observations. In the present study, we have
used opportunistic high-resolution global noncontact mapping of episodes of pacing-induced VF to address the hypothesis that in the infarcted human heart, there are regions of
myocardium that are critical for the development of VF, and
that they relate closely to regions critical to circuits that cause
reentrant VT.
Methods
Patients
Six patients (age 64.8⫾7.9 years, 3 females) undergoing ablation of
spontaneous and inducible VT who had 8 episodes of pacing-induced
VF were studied. All had poor left ventricular (LV) function
(ejection fraction 36⫾4%), previous myocardial infarction (4 anterior, 2 posterobasal), but no prior cardiac surgery (Table). Local
ethics committee approval was obtained, and patients had given
written informed consent.
Mapping Procedure
A standard quadripolar catheter was positioned at the right ventricular apex, and 2 7F mapping/ablation catheters were deployed with
a retrograde and transseptal approach. ECG and contact catheter data
were recorded on a conventional electrophysiology system. VT
induction was attempted by programmed stimulation with the
Wellens protocol.10 Entrainment mapping was performed during VT,
Received June 25, 2003; de novo received April 28, 2004; accepted May 25, 2004.
From the Imperial College and St Mary’s Hospital, London, United Kingdom.
Correspondence to Prof Nicholas S. Peters, Imperial College at St Mary’s Hospital, Department of Cardiology, Praed St, London, W2 1NY, UK. E-mail
[email protected]
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000143043.65045.CF
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Circulation
September 28, 2004
Patient Characteristics and Summary of VF Episodes
Patient
1
Age, y
55
Gender
MI
EF, %
No. of VF
Episodes
M
Anterior
35
2
2
69
M
Anterior
35
1
3
56
M
Anterior
38
2
Mode of
Induction
VTCL, ms
Pacing Rate, ms
Pacing Rate
as % of VTCL
Location of
VF Initiation*
Entrainment
275
200
73
Exit site
Entrainment
280
240
86
Exit site
Entrainment
370
260
72
Exit site
Entrainment
275
260
94
Exit site
Entrainment
290
230
79
Exit site
4
64
F
Anterior
30
1
Drive train and
extrastimuli
400-ms drive train
⫹220⫹200⫹190
Exit site
5
73
F
Posterobasal
38
1
Drive train and
extrastimuli
600-ms drive train
⫹220⫹220
VT noninducible
6
72
F
Posterobasal
40
1
Entrainment
Mean
64.8
36
296
81
7.9
4
37
8
SD
285
350
84
Remote
MI indicates myocardial infarction; EF, ejection fraction; VTCL, VT cycle length; M, male; and F, female.
*Exit site relates to VT exit site. Remote is remote from VT exit site.
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and ventricular overdrive pacing was used to terminate rapid, poorly
tolerated tachycardias.
rhythm with the introduction of up to 3 extrastimuli after a
drive train.
Noncontact Mapping
Endocardial Activation Leading to VF Induction
Noncontact mapping has been described previously.11–13 A 9F
catheter–mounted 64-wire multielectrode array was positioned inside the LV retrogradely, a 3D geometry of the LV chamber was
created, and high-resolution isopotential maps were recorded.
A common finding in all cases was that over the sequence of
paced beats, progressive extension of arcs of functional block
circumscribed areas of increasingly late activation (Figures 2
and 3). Propagation of activation through these protected
regions leading to reentry was a result of 2 processes, both
dependent on unidirectional block in part of the fully evolved
arc of functional block, which led to interaction with the main
wavefront of LV activation and associated refractoriness,
causing fragmentation into fibrillatory activation.
Definitions
Regions of scar were identified on the isopotential maps as areas of
endocardium with very low amplitude or absent reconstructed
electrograms during sinus rhythm, pacing, and VT. These areas were
then mapped with bipolar contact catheters and confirmed as scar if
electrogram amplitude was ⬍0.5 mV. VT exit sites were defined as
the point of rapidly expanding systolic activation on the isopotential
map synchronous with or just before QRS onset.
Arcs of functional block were defined as lines of block that
divided activation between adjacent endocardial areas by ⬎50 ms,
were not fixed, and varied with different rates of ventricular
activation. When present, they produced dissociated activation in
adjacent regions and electrograms with double potentials, and when
the arcs elongated to circumscribe an enlarging area of increasingly
late activation, conduction through which led to VF (see Results), the
circumscribed region was defined as the zone of VF initiation. VF
was defined by characteristic 12-lead ECG features of chaotic,
irregular, polymorphic, and rapid ventricular activation associated
with complete hemodynamic collapse that required DC cardioversion (Figure 1).
Local fibrillation intervals (consecutive maximum ⫺dV/dt in
reconstructed electrograms) were used as a surrogate measure of
local refractoriness14,15 at points on the endocardium. Intervals were
measured 2 seconds after the onset of VF for a total of 5 seconds.
Results were compared with the Mann-Whitney U test (SSPS 10
software), and values of P⬍0.05 were considered statistically
significant.
Unidirectional Block With Antegrade Conduction
By this mechanism, delayed antegrade conduction within the
circumscribed area defined by the arcs of block was suffi-
Results
All patients had at least 1 region of infarct scar identified
within the LV; 4 of these scars were located anteriorly, and 2
were posterobasal. A total of 8 episodes of pacing-induced
VF were recorded by the noncontact system in 6 patients. Six
episodes of VF occurred during continuous pacing at 81⫾8%
of VT cycle length (296⫾37 ms). The remaining 2 episodes
of VF resulted from programmed stimulation during sinus
Figure 1. Contact electrogram and 12-lead ECG showing
pacing-induced VF initiated by 2 premature extrastimuli (240
and 240 ms) after a 500-ms drive train during sinus rhythm. RVd
indicates right ventricular apex catheter, distal pole.
Chow et al
Mechanism of Pacing-Induced VF
1727
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the LV (maps 1 and 2) with no apparent lines of functional
block, confirmed by the near-simultaneous normal local
electrograms (lines 1 and 2, Figure 2C). With S3 (map 3),
lines of functional block give rise to an area of late activation
that begins in the midseptal area (asterisk, maps 3 and 4),
associated with significant slowing of conduction demonstrated by the increasing stimulus to electrogram interval
(lines 3 and 4, Figure 2C). An expanding arc of functional
block evolves with S4 (map 4), and clear double potentials
are seen on reconstructed electrograms C through E (line 4,
Figure 2C).
The first nonpaced endocardial activation is seen to arise from
the basal septum (map 5), which in this example is likely to have
arisen from deeper myocardium, although its exact origin cannot
be ascertained with noncontact mapping. Arcs of functional
block bordering an area of slow conduction form a channel for
antegrade and slow conduction (asterisk, map 5), which accounts for the split potentials (lines 5 and 6, Figure 2C). This
wavefront emerges from this protected region (the zone of VF
initiation) sufficiently late that excitability has recovered in the
surrounding myocardium (map 7), and the resulting daughter
wavelet emerges and propagates outside this protected region to
complete a cycle of reentry. The wavefront fragments into
multiple fibrillatory wavelets as it encounters fragmented lines
of functional block in the same region of late activation and
establishes VF (map 8).
Unidirectional Block With Retrograde Conduction
Figure 2. A and B, Isopotential maps showing VF initiation during pacing in sinus rhythm in patient 4. Orange dot in top right
of panel 3 represents contact artifact. C, Numbered red lines on
electrograms correspond to numbering of maps in A and B. See
text for discussion.
ciently slow that by the time activation traversed the protected region and emerged from it, excitability had recovered
in the surrounding myocardium, giving rise to a dissociated
daughter wavelet, which led to reentry. This occurred in 2 VF
episodes in 2 patients. An example of this is shown in Figure
2, which shows a sequence of noncontact data of pacinginduced VF from sinus rhythm. The flat isopotential maps
represent the entire LV cut along 1 border and laid open. The
gray area is infarct scar, and the green rectangular symbol is
the site of pacing. The purple color represents resting endocardial potential that changes through a spectrum of colors on
activation, with white representing maximal depolarization.
The black arrows show the direction of activation, and the
light blue lines represent lines of functional block. The letters
A to F on the isopotential maps are the positions of the
reconstructed electrograms in Figure 2C. A surface ECG
(lead I) is also shown with reconstructed electrograms (Figure
2C). The numbered red lines on the electrograms in Figure 2C
correspond with the numbering of the maps in Figures 2A and
2B and therefore with the points in time of these isopotential
maps.
During the last stimulus of the 600-ms drive train, activation is seen propagating uniformly from the pacing site across
The second mechanism by which fibrillatory reentry occurs is
when activation wavefronts are unable to enter a region
protected by functional lines of block antegradely and have to
propagate around the borders of block to enter the protected
region distally in a retrograde direction. The activation
wavefront propagates within this region sufficiently slowly
that the unidirectional block has recovered, and it emerges
from within the protected region to produce a daughter
wavelet, which leads to VF. This occurred in 6 VF episodes
in 4 patients.
An example of this is shown in Figure 3 (map orientation
as for Figure 2). The endocardial VT exit site is represented
by the red “Exit” label (maps 1 and 2), and site of entrainment
is represented by the red rectangular symbol. Only the exit
site and systolic portion of the circuit were mapped during
this VT, with no diastolic activity identified. During native
VT, systolic activation breaks out from a mid-posteroseptal
region and propagates across the ventricle (maps 1 and 2).
With entrainment that captures the ventricle (map 3), an area
of functional block develops close to the infarct scar (blue
line, maps 3 and 4). With subsequent entrainment beats (map
5), an expanding arc of functional block develops, giving rise
to an area of protected and late activation and slow conduction (the zone of VF initiation; asterisk, maps 5 through 8).
Activation is unable to enter the protected region antegradely,
but activation of this protected region retrogradely (map 6)
gives rise to a daughter wavelet (map 7), which emerges from
the protected area (unidirectional block) and encounters
further functional lines of block, resulting in the formation of
multiple fibrillatory wavelets that establish VF (map 8).
1728
Circulation
September 28, 2004
Figure 3. A and B, Isopotential maps showing VF
initiation during entrainment of VT in patient 1.
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Group Results
Figure 4 is a schematic representation of the LV endocardium
in all 6 patients. Infarct scar is gray, and the black pacing
symbol shows pacing site location. Patients 1 and 3 have 2
pacing symbols, which represent the position of pacing for
separate VF episodes. The ellipsoid areas are the zones of VF
initiation, and the numbered black dots are locations of the
multiple VT exit sites in each patient.
In 6 of 8 VF initiations (Figure 4, panels 1 through 4), the
locations of these critical regions occurred at scar border and
involved VT exit sites. The remaining 2 patients (panels 5 and
6) had an area that initiated VF remote from scar. These areas
had no abnormal electrogram or conduction characteristics
during sinus rhythm, pacing, or tachycardia that were predictive of initiating VF.
Two patients had 2 separate VF episodes induced during the
study (Figure 4, panels 1 and 3), both during attempted VT
entrainment. Despite different pacing site locations, both episodes of VF resulted from development of arcs of functional
block, abnormal late activation, and reentry in the same areas.
VT was induced in 5 of the 6 patients, and 4 of these 5
zones of VF initiation coincided with VT exit sites. Of the
29 VT morphologies (4.8⫾2.7 per patient), 11 VT exit
sites (35%) corresponded precisely with the region that
Figure 4. Schematic representation of LV
endocardium in all 6 patients. See text
for discussion.
Chow et al
initiated reentry and VF (ellipses with exit sites, panels 1
through 4 in Figure 4).
Measurement of Refractoriness as Estimated From
Fibrillation Intervals
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The mean duration of VF was 16⫾3 seconds, before DC
cardioversion restored patients to sinus rhythm. As a surrogate for local refractory periods, consecutive fibrillation
intervals were measured at 10 points within the region of late
activation responsible for the initiation of VF (X’s within the
ellipsoid region in Figure 4: fibrillation intervals 263⫾63 ms)
and 10 randomly selected points in a surrounding control
region (209⫾23.4 ms, P⬍0.0001; X’s outside the ellipsoid
regions in Figure 4). Thus, the estimated mean difference in
refractoriness in myocardium responsible for VF initiation
was an average of 26% (54 ms) longer than in surrounding
regions of the ventricle, which may account for the formation
of lines of functional block and slow activation of the
partially excitable tissue.
Discussion
Global high-resolution activation mapping of the development of VF in the infarcted human heart in the present study
has shown that premature extrastimuli result in the formation
of progressively expanding arcs of functional block and areas
of increasingly late activation, with reentry through part of
this functional (unidirectional) block leading to wavefront
fragmentation and the development of fibrillation wavelets.
Areas of abnormal activation responsible for the initiation of
VF are spatially related to the regions of diastolic pathways of
VT circuits, particularly the exit sites, and appear constant
regardless of the pacing site. Regions of VF initiation have
increased refractoriness compared with surrounding myocardium, which provides a possible mechanistic explanation for
the development of functional lines of block and slow
conduction, determinants of both the location and behavior of
circuits that cause VT and potentially the substrate that gives
rise to the degeneration to VF.
Reentry Causing VF
Ohara et al16 demonstrated that premature stimulation in the
infarcted canine heart results in arcs of functional block and
the development of reentry. The infarct border zone in the
canine model has been shown to be an area of relatively slow
conduction with highly heterogeneous activation times and
recovery of excitability, and this provides the substrate for the
formation of arcs of functional block that can promote reentry
and fibrillation.16 There is evidence to suggest that VF may
result from the formation of spiral waves,17–21 discontinuous
propagation of which may give rise to rotating daughter
wavelets.5,20 –23 Although the simultaneous mapping data in
the present study clearly demonstrate distinct reentrant mechanisms for the initiation of VF, a stable rotor or spiral waves
may still be implicated.
Previous studies have provided limited insight into the
mechanisms involved in the initiation of human VF. Although it is possible to fibrillate even normal hearts with
premature extrastimuli,24 the reason for the lower threshold
for inducing VF in the infarcted heart has been thought to be
Mechanism of Pacing-Induced VF
1729
due to regions with nonuniform excitability and dispersion of
refractoriness.25,26 Surface ECG recordings during episodes
of spontaneous VF have shown that closely coupled ventricular extrasystoles2 or even supraventricular ectopics27 can
provoke episodes of postinfarction VF. Josephson et al9
recorded endocardial and ECG data during pacing-induced
and spontaneous episodes of VF. It is of interest, and in
keeping with our data, that in the study by Josephson et al,9
the onset of fibrillation wavelets appeared to occur at a site
distant from the pacing site, but the lack of spatial resolution
in that study precluded further interpretation of this observation. That VF was never induced by a single extrastimulus but
always required at least 2 premature stimuli is also consistent
with the present study, in that the first stimulus is required to
condition the ventricle to the effects of the subsequent
stimulus to evolve an increasingly extensive region of block
at the critical site, or to “peel back” refractoriness of the
myocardium between the pacing site and the critical region.
The findings in the present study that fibrillation intervals are
longest in the critical region compared with surrounding
regions and that the initial paced wavefronts show progressive interaction in the critical region are in keeping with this.
Role of Functional Block in VF Initiation
With the progressive formation of arcs of functional block,
the resulting late activation emerges from the protected
region and gives rise to the daughter wavelets, initiating VF.
That the location of this fibrillatory initiation was consistent
despite different rates of activation and pacing site (2 episodes in 2 patients) indicates that it is the abnormal behavior
of a localized region of myocardium that may dictate susceptibility to VF. The characteristic features of this region are
slow conduction and late activation coupled with longer
refractory periods that predispose to the formation of the
functional lines of block and the slow conduction that
facilitates daughter wavelet formation.
Of the putative mechanisms for the development of functional conduction block,28 –30 high-resolution canine mapping
studies have provided evidence that marked regional differences in refractoriness, such as the 26% difference demonstrated in the present study, cause functional block at their
interface in an interval-dependent manner.31 Areas of VF
initiation in most of these patients had VT exit sites located
within or closely adjacent to the areas bounded by functional
block, and 6 of 8 of the regions of VF initiation were located
at the edge of the infarct scar, where fibrosis and disruption of
normal gap junctional expression have been observed32,33 and
where resulting abnormal conduction characteristics may
interact with gradients of refractoriness to promote
fibrillation.
Clinical Implications: Relationship Between VT
and VF
There is an association between areas of increased refractoriness that develop functional block, late local activation, and
wavefront fragmentation that initiates VF and the exit sites of
VT circuits. This finding gives rise to the possibility that
ablative treatment of VT circuits could modify shared substrates that initiate VF and reduce the risk of developing VF
1730
Circulation
September 28, 2004
and sudden death. Clinical evidence of this has come indirectly
from studies that show VT ablation can reduce the frequency of
VF in patients with implantable defibrillators.34 Data from the
present study provide further evidence for the influence of
functional characteristics on conduction in ventricular arrhythmogenesis and demonstrate that specific localized functional
characteristics predispose to VF. Further understanding of these
characteristics and mechanisms may allow stratification of an
individual’s risk of VF by appropriate programmed stimulation
and mapping, and may possibly enable the development of
strategies to treat VF susceptibility preemptively.
Study Limitations
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The noncontact system can only map endocardial activation;
intramural or epicardial conduction that may be important in
the genesis of VF cannot be defined. In the present study, VF
was artificially induced by programmed stimulation; whether
the same principles occur spontaneously in the degeneration
of VT to VF or in primary VF in vivo is still uncertain. In
addition, VF can also be induced in normal hearts, and
whether this or the VF that rarely occurs spontaneously
triggered by Purkinje potentials35 in an otherwise apparently
normal heart has any mechanistic features in common with
our findings in infarcted hearts remains to be determined.
Furthermore, in the present study, Purkinje potentials could
not be identified during VT or VF. The numbers of observations in this opportunistic study are small and are from a
selected patient population; there may be other mechanisms
responsible for VF initiation not seen in the present study.
Acknowledgments
Drs Chow and Segal were supported by grants from the British Heart
Foundation, including RG/2000003.
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Mechanism of Pacing-Induced Ventricular Fibrillation in the Infarcted Human Heart
Anthony W.C. Chow, Oliver R. Segal, D. Wyn Davies and Nicholas S. Peters
Circulation. 2004;110:1725-1730; originally published online September 20, 2004;
doi: 10.1161/01.CIR.0000143043.65045.CF
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